Project Summary The objective of this application is to identify biomarkers in Huntington's disease (HD) in a noninvasive way, with the hope that these insights will eventually lead to the development of tools that guide clinical diagnosis and aid drug development. HD is a fatal inherited disorder that progresses for 15-20 years after symptom onset. The mutation that causes HD is a variable expansion of CAG repeats encoding polyglutamine (polyQ) in the huntingtin (Htt) protein. As there is no therapy for this hereditary neurodegenerative disease, further effort should be made to slow the progression of neurodegeneration in patients through the definition of early therapeutic interventions. For this purpose, molecular biomarkers for monitoring disease onset, disease progression, and response to treatment need to be identified. However, the non-invasive detection of clinically useful biomarkers is a challenge faced by many research laboratories. Mitochondrial dysfunction precedes neuropathology and clinical symptoms in patients with HD, indicating that mitochondrial impairment is an early event in the cascade leading to HD pathogenesis. Thus, ability to monitor alteration of mitochondrial function during HD development may allow us to identify biomarkers for disease progression and for therapeutic response. Using targeted metabolomics, preliminary studies identified a panel of mitochondrial intermediates that were changed in the plasma of HD transgenic mice before the appearance of neuronal degeneration. Moreover, some of these mitochondrial substrates were consistently changes in patient CSF and responded to the treatment in HD mice at the early stage of disease progression. These preliminary data have led us to formulate the central hypothesis that markers reflecting mitochondrial dysfunction in peripheral blood are a characteristic pathophysiological factor of HD pathology and provide a novel and noninvasive way to monitor HD disease progression. The significance for the proposed research is that the establishment of mitochondrial signatures as a panel of candidate biomarkers will allow for further validation in a larger cohort of patients on whether these biomarkers could be used for detecting disease state and assessing the efficacy of therapies. In Aim 1, we will test the hypothesis that alteration of mitochondrial metabolic intermediates in HD patient plasma and CSF provides biomarkers amenable for tracking HD disease progression. In Aim 2, we will test the hypothesis that treatment can correct the aberrant mitochondrial intermediates in the plasma and CSF of HD transgenic mice, amenable for treatment efficacy. By the end of this study, we anticipate that we will have a method of identifying mitochondrial biomarkers to indicate HD disease progression; and that we will have a proof of principle that altered plasma and CSF mitochondrial metabolic intermediates can be used to monitor treatment efficacy of experimental drugs for HD.